Psoriasis is a common, chronic, cytokine driven inflammatory and hyper-proliferative skin disease associated with significant cardiovascular and metabolic co-morbidities. Major progress has been made in recent years delineating genetic risk factors predisposing to psoriasis through genome-wide association studies (GWAS), with 41 susceptibility loci identified to date. The clinical importance of these findings is underscored by the fact that several risk loci point to pathways and molecules already targeted for the treatment of psoriasis. More importantly, the GWAS results have the potential to identify previously unappreciated pathways, which may be critical in the disease pathogenesis and therefore ideal therapeutic targets. One of these risk variants is located within the IL13 gene, but the role of IL 13 in psoriasis pathogenesis is mostly unknown. However, several lines of evidence, including our own preliminary data, point towards a major role for IL-13 in psoriasis, setting the stage for our hypothesis that IL-13 has a pro-inflammatory role in the pathogenesis of psoriasis by potentiating Th1 and Th17 induced skin inflammation. The objective of this proposal is to define the pathogenic role of IL-13 in psoriasis, elucidate the critical pathways and mechanisms involved, and assess the impact of the psoriasis-associated IL13 rs20541 risk variant on inflammation in psoriatic skin. This project will provide new data on an unappreciated and understudied inflammatory pathway in the pathogenesis of psoriasis, it will assess the potential of targeting IL-13 or its receptor system in psoriasis, and ultimately lead the way towards more effective treatments for patients with this chronic, and often, devastating disease.